Cellular damage caused by reactive oxygen species (ROS) is thought to play a role in numerous late onset diseases such as Parkinson's, Alzheimer's and cancer. In addition, enhanced organismal longevity itself has been associated with increased resistance to ROS and the free radical theory of aging postulates that it is the accumulation of ROS induced cellular damage that leads to the decline in various organ systems with age. A molecular understanding of the critical cellular responses to ROS has suffered from lack of a detailed genetic dissection of the process. Moreover, few animal models exist in which to test the impact of alteration in the cellular response to ROS at an organismal level. The current proposal uses screening in primary fibroblasts derived from mice carrying random ENU induced recessive mutations. The goal is to isolate single gene mutations that lead to either enhance or reduced resistance to ROS in the cultured fibroblasts. This approach allows for an unbiased genetic dissection of the cellular response to ROS induced damage and provides animal models with altered sensitivity to ROS, at least in one cell type, that are immediately available for aging studies. Although beyond the scope of this pilot grant, any heritable mutants will ultimately be positionally cloned to identify the molecular determinants of the observed phenotype.